Rational refinement and targeting of therapies for Parkinson's disease (PD) will be facilitated by an ability to analyze relationships between the pathologic features of the disease and symptoms. Neurotoxin models, however, are limited in their ability to break down the disease into its component features. This problem is exacerbated by two complications that are coming to greater recognition: 1) loss of dopamine (DA) is by no means restricted to the striatum in idiopathic PD or in neurotoxin models of the disease;and 2) individual DA neurons innervate multiple brain regions. We propose a monkey model for studying the pathologic underpinnings of parkinsonism that overcomes the hurdles presented by these complications. Reversible intracerebral blockade of DA neurotransmission will afford precise control over the location of DA loss/blockade, its spatial extent and severity, and its timecourse. It is precisely these aspects of DA dysfunction that are difficult if not impossible to control using neurotoxins. The proposed experiments will use DA antagonists to address the central, yet persistent, question whether loss of DA from the striatum alone can generate the cardinal signs of PD. Although akinesia, bradykinesia, tremor and rigidity are commonly attributed to striatal loss of DA, idiopathic PD and neurotoxin-induced parkinsonism are marked by DA loss in other structures as well. The first aim will determine if these signs can be reproduced in primates by transient antagonism of DA receptors (both D1 and D2) in the motor striatum. Convection-enhanced delivery will be used to produce a homogeneous blockade of DA receptors within significant portions of the posterior putamen (site of the most severe DA loss in idiopathic PD). Parkinsonian signs will be measured using tasks designed to manipulate relevant behavioral parameters: movement initiation/sequencing (akinesia), movement kinematics (bradykinesia), tremor, and muscle tone (rigidity). The internal globus pallidus is a critical link in the translating the DA dysfunction of PD into parkinsonian signs. The second aim will determine which abnormalities in the firing of globus pallidus neurons can be attributed directly to the loss of striatal DA and thus contribute to the impairments elicited. This aim will also correlate specific abnormalities in pallidal firing with the appearance of specific parkinsonian symptoms. PUBLIC HEALTH RELEVANCE: Despite the growing prevalence of Parkinson's disease in the population, refinement and accurate anatomical targeting of new treatments is impeded by our rudimentary understanding of the relationship between the pathology of the disease (i.e., which cells die) and its symptoms. The animal model and experiments proposed here will provide important new information about the critical pathologic defects that give rise to parkinsonian signs. Target selection for new cell and gene therapies will be guided by this information.